We have found strong evidence for linkage of schizophrenia to chr. 5q13 in a large high-density pedigree from a genetic isolate in the central mountain region of Puerto Rico. A genome scan in this family revealed a multipoint lodscore of 4.8 and we have been able to narrow the minimal critical interval (MCI) for a schizophrenia susceptibility locus to 2.8 Mb containing 13 reference genes. The major goal of this proposal is to screen those reference genes by sequencing exons, exon-flanking intronic regions, 3. untranslated (3.UTR) and putative promoter regions. The frequency of clear protein-altering mutations will be examined in an independent sample of 200 cases and controls from the same region in Puerto Rico. If only synonymous and other variants segregate with the disease in this large pedigree, we will use LD mapping in the independent Puerto Rican case-control sample to either assess the disease risk for these variants or for guidance to identify variances in non-coding regions under the LD peak. Prior independent evidence for suggestive linkage for schizophrenia to 5p13 has been reported by several studies and this same region has recently received renewed attention after genome wide linkage analysis of 409 families with schizophrenia, however, the MCI remained large (31.8 cM), even after narrowing this region by fine mapping. Our Puerto Rican family therefore offers the opportunity to identify genes within the 5p13 region that might contribute to schizophrenia not only in Puerto Ricans but also in other populations.